Abstract C061: GNL3 promotes prostate cancer growth by regulating androgen receptor protein stability

Abstract

Abstract Androgen receptor (AR) is a primary driver of prostate cancer growth and development. Changes in AR coregulatoractivity or expression have severe consequences on the development of the disease. Using ChIP-MS, we discover G Protein Nucleolar 3 (GNL3) as a new AR transcriptional coactivator. We show that GNL3 helps the recruitment of AR to chromatin to directly control genes that support prostate cancer growth. We also demonstrate that GNL3 stabilizes AR by protecting it from ubiquitination and proteasomal degradation. We further determine that GNL3 is required for tumor progression by preventing cell-cycle arrest and apoptosis. Moreover, depleting GNL3 causes prostate cancer cells to be more susceptible to AR antagonists. Our work also indicates that Palbociclib, a CDK4/6 inhibitor, can be combined with enzalutamide to suppress cancer cell growth by downregulating AR and GNL3 co-regulated genes. From patient analyses, we observe that GNL3 expression is significantly elevated in many clinical studies. Finally, we reveal an AR-GNL3 gene signature in prostate tumors that is highly expressed and predicts disease recurrence. In summary, our results highlightthat GNL3 is a novel coactivator of AR and a potential target for the treatment of prostate cancer. Citation Format: Edwin Cheung, Cuiting Zhang. GNL3 promotes prostate cancer growth by regulating androgen receptor protein stability [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C061.